Abstract LSUHSC CARC Overall The Louisiana State University Health Sciences Center New Orleans (LSUHSC-NO) Comprehensive Alcohol- HIV/AIDS Research Center (CARC) is a multi-institutional, multidisciplinary team of scientists from LSUHSC and the Tulane National Primate Research Center (TNPRC) and School of Public Health and Tropical Medicine (TSPHTM) with a research focus on the interaction of alcohol use disorder (AUD), human immunodeficiency virus (HIV), and antiretroviral therapy (ART). The translational focus is the impact of at-risk alcohol consumption on risk for comorbidities in a longitudinal cohort of in-care virally-suppressed persons living with HIV (PLWH). We have demonstrated the relevance of the simian immunodeficiency virus (SIV) nonhuman primate (NHP) model to the clinical setting, revealed the deleterious impact of alcohol despite viremic control in in-care PLWH, and identified environmental (neighborhood) and behavioral (diet) factors that affect disease course and severity. The proposed studies evolve, expand, and refine our research strategy to a mechanistic bidirectional (NHP? PLWH?NHP) translational investigation of the impact of AUD, HIV, and ART on comorbid conditions in an underserved cohort of PLWH. The scientific premise of the proposed studies is the observation that intestinal mucosa is an early site of alcohol-induced immunopathogenic changes in the alcohol-consuming, HIV/SIV- infected host that culminates in loss of mucosal barrier function and gut leak that promotes chronic immune activation, inflammation, and senescence, which we hypothesize increases risk for comorbidities in PLWH. An Administrative Core provides oversight, supports data management and analysis, and funds pilot projects to promote novel research investigations. Four Research Components (RCs) study in-care underserved PLWH and a sex- and age-matched HIV- control group, complemented by mechanistic studies in SIV+ and SIV- NHPs. RC1 investigates the impact of community and interpersonal stress on behavioral and chronic comorbidities among PLWH and the unique role that alcohol consumption plays in the pathways. RC2 and RC3 elucidate pathophysiological mechanisms of two comorbidities: metabolic dysregulation and neurological deficits. RC4 investigates the immunological mechanisms driving the balance between immune activation and activation- induced cell death that contribute to cell senescence and tissue injury with alcohol exposure. An Experimental and Analytical Resource Core provides support for all proposed studies. An Information Dissemination Core promotes training and accelerates the translation and dissemination of research findings to the scientific, health care, and lay communities. The CARC will continue to leverage and synergize with existing institutional resources. Access to a unique HIV+ population in a southeast urban region, the established expertise of CARC investigators in biomedical and behavioral research, state-of-the-art research facilities, outstanding scientific environment, and strong institutional support will ensure that the proposed CARC projects will continue to advance our understanding of the comorbid consequences of AUD, HIV/SIV, and ART in PLWH.